Ketone Administration for Seizure Disorders: History and Rationale for Ketone Esters and Metabolic Alternatives
The ketogenic diet (KD) is a high-fat, low-carbohydrate treatment for medically intractable epilepsy. One of the hallmark features of the KD is the production of ketone bodies which have long been believed, but not yet proven, to exert direct anti-seizure effects. The prevailing view has been that ketosis is an epiphenomenon during KD treatment, mostly due to clinical observations that blood ketone levels do not correlate well with seizure control. Nevertheless, there is increasing experimental evidence that ketone bodies alone can exert anti-seizure properties through a multiplicity of mechanisms, including but not limited to: (1) activation of inhibitory adenosine and ATP-sensitive potassium channels; (2) enhancement of mitochondrial function and reduction in oxidative stress; (3) attenuation of excitatory neurotransmission; and (4) enhancement of central γ-aminobutyric acid (GABA) synthesis. Other novel actions more recently reported include inhibition of inflammasome assembly and activation of peripheral immune cells, and epigenetic effects by decreasing the activity of histone deacetylases (HDACs). Collectively, the preclinical evidence to date suggests that ketone administration alone might afford anti-seizure benefits for patients with epilepsy. There are, however, pragmatic challenges in administering ketone bodies in humans, but prior concerns may largely be mitigated through the use of ketone esters or balanced ketone electrolyte formulations that can be given orally and induce elevated and sustained hyperketonemia to achieve therapeutic effects.
Considering the multifaceted therapeutic effects and success of the KD for seizure disorders, the goal of many ketone supplement researchers has often been described as creating “the KD in a pill.” As such, exogenous ketone supplements are being developed as an alternative or adjuvant method of inducing therapeutic ketosis without the need for a strict dietary regimen. Considering the promising results of the recent pre-clinical studies described here, along with advancements in optimizing ketone supplement formulations, it is possible that many of the seizure conditions which are known to benefit from the KD could receive some benefit from exogenous ketone supplementation by elevating blood ketones and lowering blood glucose. Importantly, if ketone supplements prove safe and efficacious in human trials, they may provide a tool for achieving ketosis in patients who are unable, unwilling, or uninterested in consuming a classic KD, modified Atkins diet, or LGIT. Ketone supplementation may also help circumvent some of the difficulties associated with dietary therapy, as it allows for a rapid dose-dependent induction of ketosis, which can be sustained with prolonged consumption and monitored precisely with commercially available technologies (e.g., blood ketone meters). Simultaneously, it could provide patients with the opportunity to reap the benefits of therapeutic ketosis without the practical and social difficulties of a highly restrictive diet. Moreover, these agents may represent a means to further enhance or optimize existing ketogenic therapies by supplying a form of non-glycemic calories that improves parameters (e.g., GKI) that are associated with therapeutic benefits.
Research on the potential applications of ketone supplementation is rapidly growing, and there are currently several registered clinical trials evaluating their safety and efficacy in a variety of conditions, including healthy adults, athletes, and patients with various diseases including Alzheimer’s, Parkinson’s, Type 2 Diabetes Mellitus, and more1. Encouragingly, clinical studies evaluating these agents in seizure disorders are beginning to emerge. An ongoing trial in Angelman syndrome – a genetic neurodevelopmental disorder characterized intellectual and developmental disability and seizures – is evaluating the use of a fat-based nutritional formulation containing exogenous ketones to support nutritional needs of this patient population (NCT03644693). As a secondary outcome measure, the investigators will also be tracking changes in EEG and seizure activity. Anecdotal reports of individuals consuming commercially available ketone supplements have suggested that some individuals experience a subjective improvement in seizure activity with their use, despite the fact that some of the more potent formulations, such as BD-AcAc2, are not yet commercially available. Regardless, it is important to highlight that there is a lack of published clinical work demonstrating efficacy of such agents in patients with seizure disorders, and the relationship between blood ketone elevation and the protective effects of ketosis on seizures is unclear. Thus, further research is needed to fully investigate the molecular mechanisms, clinical utility, and feasibility of exogenous ketone supplements as a method of inducing therapeutic ketosis for managing seizures.